Chromosome 22q11.2 deletion syndrome is the most common chromosome microdeletion syndrome in human beings and results in multiple medical problems and neurocognitive deficits. These neurocognitive deficits adversely affect functions that are critical to these children's success in academic tasks and in daily life. Additionally, these children face an extraordinarily high risk of schizophrenia and other debilitating mental illnesses as adolescents and adults. During the course of these mental illnesses, the pre-existing cognitive deficits become worse and add to the handicaps that they face. Thus, there is an urgent need for interventions to reduce the burden of the neurocognitive deficits upon these individuals and to increase their functionality. A critical first step to designing an intervention is to understand the mechanisms of the cognitive deficits and in this proposal the PI, Dr. Shashi will acquire the necessary skills to understand the neuronal function and structure related to working memory in children with 22q11DS. The aims are as follows: Specific Aim 1: Ascertain neuronal areas activated by the use of working memory in children with 22q11DS. This aim is based on hypothesis 1 which is that children with 22q11DS will have decreased activation patterns in the dorsolateral prefrontal cortex (DLPFC), cingulate and parietal areas of the brain with a working memory task, compared to control subjects. Specific Aim 2: Examine the patterns of structural connectivity of white matter in the areas activated by working memory in children with 22q11DS. This is based on hypothesis 2 which is that children with 22q11DS will have reduced neuronal integrity in and reduced connectivity between the DLPFC, cingulate and parietal areas, compared to control subjects. In order to achieve these aims, Dr.Shashi will spend the first 6 months of this award period to acquire training in the fields of functional magnetic resonance imaging and diffusion tensor imaging, which would allow her to examine the areas of the brain that are activated when working memory is used and the white matter connections between these areas. This training will occur under the mentorship of Drs. Allen Song of Duke University and Matcheri Keshavan of Harvard Medical School. This project will provide information about the basis of working memory in children with 22q11DS and a framework upon which the efficacy of interventions can be assessed in the future. PUBLIC HEALTH RELEVANCE: Understanding neuronal correlates of working memory in children with 22q11DS will help to provide a way to assess improvements after interventions to improve working memory.